What are the genetic associations between modifiable risk factors and Alzheimer’s disease?

In a recent study published in JAMA Network is openIn this study, the researchers conducted a genetic association study using the Mendelian Randomization (MR) framework to assess associations between genetically modifiable risk factors, such as high-density lipoprotein (HDL) cholesterol, systolic blood pressure (SBP), and Alzheimer’s disease (AD).

They worked with a large genomic dataset, the European Alzheimer’s and Dementia Biobank (EADB), which includes 39,106 participants with a clinical diagnosis of Alzheimer’s disease and 401,577 participants without Alzheimer’s disease.

background

According to recent estimates, the prevalence of dementia may triple by 2050. According to other scientific reports, 40% of dementia cases can be prevented simply by adjusting 12 risk factors.

Thus, knowledge of the genetic basis of associations between modifiable risk factors and dementia could inform preventive and therapeutic strategies for dementia, including Alzheimer’s.

Both observational studies and randomized clinical trials (RCTs) have identified associations between risk factors and dementia. However, their findings remained limited and were not equivalent to causation.

Conversely, MR design uses genetic variants to find potential causal relationships between modifiable risk factors and dementia outcomes.

The MRI approach can also guide whether comprehensive randomized trials are meaningful or necessary.

Genome-wide association studies (GWAS) have only been performed for Alzheimer’s disease, the most common type of dementia. These studies have found inconclusive evidence of associations between blood pressure (BP), body mass index (BMI), smoking, and alcohol consumption as risk factors for Alzheimer’s disease.

Because many biases and study designs may have an impact on the results of these studies, there is a need for more robust MR studies to test genetic associations between AD and modifiable risk factors.

about studying

In this study, the researchers used a univariate and multivariate two-sample MR framework to conduct a genetic association study to identify potential causes of modifiable risk factors for AD to inform the development of new drugs for the prevention of AD.

They chose independent genetic variants related to these factors as useful covariates to fetch the primary outcome data for AD for each EADB as odds ratios (ORs) and 95% confidence intervals (CIs).

To reconcile estimates of associations between genetic variants, risk factors, and Alzheimer’s disease on the same allele, the team reconciled the estimates and removed ambiguous variants.

For the primary study analysis, they used the inverse variance weighting (IVW) method, which combines estimates of single-nucleotide variants (SNV)-specific computed using Wald pedigree.

This method works on the assumption that the main MR assumptions are not violated and, therefore, limits interceptions to zero.

On the contrary, the MR-Egger method is statistically less efficient, i.e. it produces wider confidence intervals but provides a causal estimate accounting for horizontal polymorphism.

Similarly, they performed a multivariate MR to estimate associated risk factors, for example, apoA1 and apoB, which are associated with HDL and LDL, respectively. In this way, they obtained the direct effect of exposure for each factor in the model without confusion.

The team performed four additional sensitivity analyses. Notably, they conducted all study analyzes between April 12 and October 27, 2022.

results

In the EADB-diagnosed cohort, 39,106 and 4,015,77 participants were clinically diagnosed with Alzheimer’s disease but not AD, respectively. The average age of the participants with Alzheimer’s disease ranged from 72 to 83 years, and 54% to 75% of the participants were female.

Similarly, the average age of the control participants ranged from 51 to 80 years, and 48% to 60% of them were female.

Genetically confirmed levels of HDL cholesterol have been associated with an increased odds of developing Alzheimer’s disease. Accordingly, the authors or for each 1-SD observed an increase of 1.10 [95% CI]. Genetically determined elevated systolic blood pressure was associated with an increased risk of Alzheimer’s disease after accounting for diastolic blood pressure, the odds ratio for each 10 mmHg increase was 1.22 [95% CI].

In a second analysis, the authors excluded the entire UK Biobank from the EADB consortium to reduce bias due to overlapping sampling. However, the odds of developing Alzheimer’s disease remained comparable for HDL cholesterol and systolic BP, with an OR per SD unit increase of 1.08 and an OR per 10 mmHg increase of 1.23, respectively.

In general, genetically determined high HDL cholesterol levels and high SBP increased the likelihood of developing Alzheimer’s disease.

conclusions

According to the authors, this is the first study to identify an association between elevated HDL cholesterol levels and a higher risk of Alzheimer’s disease in a wide range of supplement analyses.

The genetic tools for high-density lipoprotein cholesterol used in this study, for example, cholesterol ester transport protein, and hepatic lipase, to name a few, further validated the study findings.

Because the genetic associations identified are new, the study findings may inspire the development of new drug therapies to prevent dementia, including Alzheimer’s disease, and to diagnose dementia at an early stage.